Upper airway lengthening caused by weight increase in obstructive sleep apnea patients.

BACKGROUND: The longer upper airway is more collapsible during sleep. This study aims to reveal relationships among upper airway length, weight, and obstructive sleep apnea (OSA), particularly to answer why the upper airway of OSA patients is longer than that of healthy people and why some obese people suffer from OSA while others do not. METHODS: We perform head and neck MRI on male patients and controls, and measure > 20 morphological parameters, including several never before investigated, to quantify the effect of weight change on upper airway length. RESULTS: The upper airway length is longer in patients and correlates strongly to body weight. Weight increase leads to significant fat infiltration in the tongue, causing the hyoid to move downward and lengthen the airway in patients. The apnea-hypopnea index (AHI) strongly correlates to airway length and tongue size. Surprisingly, a distance parameter h and angle ß near the occipital bone both show significant differences between healthy males and patients due to their different head backward tilt angle, and strongly correlates with AHI. The contributions of downward hyoid movement and head tilt on airway lengthening are 67.4-80.5% and19.5-32.6%, respectively, in patients. The parapharyngeal fat pad also correlates strongly with AHI. CONCLUSIONS: The findings in this study reveal that the amount of body weight and distribution of deposited fat both affect airway length, and therefore OSA. Fat distribution plays a larger impact than the amount of weight, and is a better predictor of who among obese people are more prone to OSA.

A pilot study in men to show the effects of postural fluid shifts on the severity of obstructive sleep apnea.

PURPOSE: Studies reveal that rostral fluid shifts due to body posture changes from standing to lying down may narrow the upper airway. However, without credible and direct experimental evidence, it remains unclear what the role of natural fluid redistribution in the neck is in affecting obstructive sleep apnea (OSA) severity. Our aim is using direct experimental evidence to determine whether or not postural fluid shifts affect OSA severity. METHODS: We performed overnight polysomnography on two consecutive nights for 22 men. The bed was set horizontally on the control night, while its tail part was lowered by 30° on the experimental night to reduce the amount of fluid shifted into the neck. We measured sleep and anthropometric parameters on each night. RESULTS: The mean (95% CI) apnea-hypopnea index (AHI) in the supine head and trunk position decreased from 66.6 events per hour (57.6-75.6) to 61.2 (52.0-70.4) (t = 4.507, p <0.001), and the oxygen desaturation index from 69.5 events per hour (56.4-82.6) to 61.6 (50.5-72.6) (t = 3.293, p = 0.004), from the control to the experimental night with a decrease in the change of leg fluid volume from 17.7% (15.7-19.8) to 4.7% (1.9-7.5) (t = 11.659, p < 0.001). CONCLUSIONS: Our findings provide direct experimental evidence to show that natural fluid shift caused by the day-to-night posture change does contribute to OSA pathogenesis and severity. It is likely that the neck fluid increase from an actual day-to-night position change, with 90° change in posture, would produce a much larger AHI increase than the 11.2% found in this study, which contains only a 30° change in posture. These findings suggest that reducing the amount of fluid in the neck region may relieve airway obstructions for patients with moderate and severe OSA.

Threshold of the upper airway cross-section for hypopnea onset during sleep and its identification under waking condition.

BACKGROUND: There is currently no method that can predict whether or under what condition hypopnea, even obstructive sleep apnea (OSA), will occur during sleep for individuals based on credible parameters measured under waking condition. We propose a threshold concept based on the narrowest cross-sectional area of the upper airway (CSA-UA) and aim to prove our hypothesis on the threshold of the area for hypopnea onset (TAHO), which can be used as an indicator of hypopnea onset during sleep and measured while awake. METHODS: We performed magnetic resonance imaging for 20 OSA patients to observe CSA-UA changes during fluid accumulation in the neck caused by elevating their legs, and identified TAHO by capturing the sudden enlargement in CSA-UA. Correlation analyses between TAHO and the body mass index (BMI), and between the reduction in CSA-UA and the increase in the neck circumference (NC) with fluid accumulation were performed. Logistic regression analysis was performed for identifying OSA patients based on the behaviors of their CSA-UA changes during leg raising. Shape changes of airway cross-section were also investigated. RESULTS: Four CSA-UA change patterns after fluid redistribution were identified. Six patients had similar CSA-UA variation behaviors observed in healthy subjects. From the other three change patterns involving 14 patients, a threshold value of CSA-UA 0.63 ± 0.21 cm2 was identified for normal breathing. Data showed a positive correlation between TAHO and BMI (r = 0.681, p = 0.0007), and a negative correlation between the reduction in CSA-UA and the increase in NC (r = - 0.513, p = 0.051) with fluid accumulation. A sigmoid function for the probability of being a OSA patient p = 1/[1 + exp. (4.836 + 3.850 t-8.4 h)] was obtained to effectively separate OSA patients from normal subjects. The upper airway narrowing occurred in anteroposterior, lateral, or both directions, suggesting different tendencies of upper airway collapse in patients. Three types of shape changes in the cross-section of the upper airway, which had different effects on airway resistance, were measured. CONCLUSIONS: Our findings prove TAHO hypothesis. The threshold measured while awake for normal breathing can be used clinically as the indicator of hypopnea onset during sleep, and therefore to identify OSA patients under waking condition and design effective personalized treatments for OSA patients. Both shape and size changes in the cross-section of the upper airway affect airway resistance significantly. Shape change in the cross-section of the upper airway can provide key clinical information on the collapse patterns of the upper airway for individuals.

Discovery of novel simplified isoxazole derivatives of sampangine as potent anti-cryptococcal agents.

Cryptococcus neoformans is the leading cause of cryptococcal meningitis, which is associated with high mortality due to lack of effective treatment. Herein a series of tricyclic isoxazole derivatives with excellent anti-cryptococcal activities were identified by structural simplification and scaffold hopping of antifungal natural product sampangine. Particularly, compound 8a showed promising features as an anti-cryptococcal lead compound. It was highly active against C. neoformans (MIC80 = 0.031 µg/mL), which was more potent than fluconazole and voriconazole. Moreover, compound 8a showed potent fungicidal activity and had potent inhibitory effects against important virulence factors (i.e. biofilm, melanin and urease) of C. neoformans. Preliminary antifungal mechanism investigation revealed that compound 8a induced apoptosis of C. neoformans cells and arrested the cell cycle at the G1/S phase.

Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran-oxindole derivatives as potent p53-MDM2 inhibitors.

p53-MDM2 protein-protein interaction is a promising target for novel antitumor drug development. Previously, we identified a new class of spirotetrahydrothiopyran-oxindole p53-MDM2 inhibitors by novel organocatalytic enantioselective cascade reactions. Herein, a series of new derivatives were designed, synthesized and assayed to investigate the structure-activity relationships. Among them, compound B14 bearing a novel spiroindole-thiopyranopyridone scaffold exhibited potent MDM2 inhibitory activity as well as antitumor activity, which could effectively induce the apoptosis of A549 cancer cells. It represents a promising lead compound for the development of novel antitumor agents.

Time delays between physiological signals in interpreting the body's responses to intermittent hypoxia in obstructive sleep apnea.

Objective.Intermittent hypoxia, the primary pathology of obstructive sleep apnea (OSA), causes cardiovascular responses resulting in changes in hemodynamic parameters such as stroke volume (SV), blood pressure (BP), and heart rate (HR). However, previous studies have produced very different conclusions, such as suggesting that SV increases or decreases during apnea. A key reason for drawing contrary conclusions from similar measurements may be due to ignoring the time delay in acquiring response signals. By analyzing the signals collected during hypoxia, we aim to establish criteria for determining the delay time between the onset of apnea and the onset of physiological parameter response.Approach.We monitored oxygen saturation (SpO2), transcutaneous oxygen pressure (TcPO2), and hemodynamic parameters SV, HR, and BP, during sleep in 66 patients with different OSA severity to observe body's response to hypoxia and determine the delay time of above parameters. Data were analyzed using the Kruskal-Wallis test, Quade test, and Spearman test.Main results.We found that simultaneous acquisition of various parameters inevitably involved varying degrees of response delay (7.12-25.60 s). The delay time of hemodynamic parameters was significantly shorter than that of SpO2and TcPO2(p< 0.01). OSA severity affected the response delay of SpO2, TcPO2, SV, mean BP, and HR (p< 0.05). SV delay time was negatively correlated with the apnea-hypopnea index (r= -0.4831,p< 0.0001).Significance.The real body response should be determined after removing the effect of delay time, which is the key to solve the problem of drawing contradictory conclusions from similar studies. The methods and important findings presented in this study provide key information for revealing the true response of the cardiovascular system during hypoxia, indicating the importance of proper signal analysis for correctly interpreting the cardiovascular hemodynamic response phenomena and exploring their physiological and pathophysiological mechanisms.

Mechanical mechanism to induce inspiratory flow limitation in obstructive sleep apnea patients revealed from in-vitro studies.

Inspiratory flow limitation means that when the flowrate reaches a certain value, it no longer increases, or even decreases, which is called negative effort dependence flow limitation, even if the inspiration effort is increased. This occurs often in obstructive sleep apnea patients, but its mechanism remains unclear. To reveal the mechanism of inspiratory flow limitation, we constructed a unique partially collapsible in-vitro upper airway model of obstructive sleep apnea patients to observe the change of airway resistance with inspiratory driving pressure. The important findings demonstrate that with the increase of inspiratory effort, the driving pressure increases faster than the airway resistance in the early stages, and then the reverse occurs as the airway becomes narrower. The airway collapse caused by the transmural pressure can lead to a rapid increase in downstream resistance with the increase of inspiratory effort, which is the key reason causing the flow reduction and the formation of typical negative effort dependence flow limitation. The mechanical mechanism revealed in this study will lead to fully new insights into the study and treatment of obstructive sleep apnea.

Characteristics and Mechanism of Upper Airway Collapse Revealed by Dynamic MRI During Natural Sleep in Patients with Severe Obstructive Sleep Apnea.

Purpose: Upper airway collapse during sleep in patients with obstructive sleep apnea (OSA) is a complex and dynamic phenomenon. By observing and analyzing the dynamic changes in the upper airway and its surrounding tissues during airway obstruction, we aim to reveal dynamic characteristics in different obstruction patterns, and the relationship between anatomical features during normal breathing and dynamic characteristics of airway obstruction. Patients and Methods: Dynamic MRI was performed in 23 male patients (age range 26-63) with severe OSA diagnosed by overnight polysomnography, and obstruction events were identified from their images. Dynamic changes in parameters of the upper airway and surrounding tissues were measured to assess the key characteristics in different obstruction patterns. Results: We categorized airway obstruction into four types based on the obstruction location and motion characteristics of tissues during collapse, and detailed the alterations in the airway and surrounding tissues under each obstruction pattern. In all 112 obstruction events extracted from the dynamic images of 23 patients, type A (retropalatal obstruction caused by the soft palate separated from the tongue), BI, BII (both retropalatal obstructions caused by the soft palate attached to the tongue, and C (retropalatal and retroglossal obstruction caused by the soft palate and the tongue), accounted for 28.6%, 44.6%, 12.5%, and 14.3% respectively. In severe OSA patients with tongue and palatal obstruction related to type B or C, the more posterior hyoid position, shorter distance between tongue and uvula, and wider retropalatal space, the larger the tongue displacement and deformation during collapse, and the greater the reduction in airway space. Conclusion: There are multiple airway obstruction patterns, each with its own anatomical characteristics and behaviors during collapse. Hyoid position, tongue and uvula distance, and retropalatal space play an important role in airway collapse and should be paid more attention in the treatment of OSA.

Discovery of Novel Sertraline Derivatives as Potent Anti-Cryptococcus Agents.

Treatment of life-threatening cryptococcal meningitis (CM) is highly challenging due to the limited efficacy of the available antifungal drugs. Antidepressant sertraline (SER) has been proposed to be a potential antifungal agent for CM. However, clinical studies indicated that SER failed to achieve the expected therapeutic effects. Herein, novel SER derivatives were designed by scaffold hopping, and they showed improved anticryptococcal activity both in vitro and in vivo. In particular, compound D16 was identified as a promising anti-CM agent with a new antifungal mode of action. It acted by blocking the biosynthesis of ergosterol through the inhibition of Δ5,6-desaturase. This study provides a new target and a drug-like candidate for CM treatment.

In Vitro Study of Endothelial Cell Morphology and Gene Expression in Response to Wall Shear Stress Induced by Arterial Stenosis.

Objectives: We examined the correlation between changes in hemodynamic characteristics induced by arterial stenosis and vascular endothelial cell (EC) morphology and gene expression in straight silicone arteries. Materials and methods: Transparent silicone straight artery models with four degrees of stenosis (0, 30, 50, and 70%) were fabricated. Particle image velocimetry was performed to screen silicone vessel structures with good symmetry and to match the numerical simulations. After the inner surface of a symmetric model was populated with ECs, it was perfusion-cultured at a steady flow rate. A computational fluid dynamics (CFD) study was conducted under the same perfusion conditions as in the flow experiment. The high-WSS region was then identified by CFD simulation. EC morphology in the high-WSS regions was characterized by confocal microscopy. ECs were antibody-stained to analyze the expression of inflammatory factors, including matrix metalloproteinase (MMP)-9 and nuclear factor (NF)-κB, which were then correlated with the CFD simulations. Results: As the degree of vascular stenosis increases, more evident jet flow occurs, and the maximum WSS position moves away first and then back. ECs were irregularly shaped at vortex flow regions. The number of gaps between the cells in high-WSS regions increased. The MMP-9 and NF-κB expression did not differ between vessels with 30 and 0% stenosis. When arterial stenosis was 70%, the MMP-9 and NF-κB expression increased significantly, which correlated with the regions of substantially high WSS in the CFD simulations. Conclusion: Stenotic arteries induce hemodynamic stress variations, which contribute to differences in EC morphology and gene expression. A high degree of vascular stenosis can directly increase inflammatory factor expression.

Discovery of Piperidol Derivatives for Combinational Treatment of Azole-Resistant Candidiasis.

Effective strategies are needed to deal with invasive fungal infections caused by drug-resistant fungi. Previously, we designed a series of antifungal benzocyclane derivatives based on the drug repurposing of haloperidol. Herein, further structural optimization and antifungal mechanism studies were performed, leading to the discovery of new piperidol derivative B2 with improved synergistic antifungal potency, selectivity, and water solubility. In particular, the combination of compound B2 and fluconazole showed potent in vitro and in vivo antifungal activity against azole-resistant Candida albicans. Compound B2 inhibited important virulence factors by regulating virulence-associated genes and improved the efficacy of fluconazole by down-regulating the CYP51-coding gene and efflux pump gene. Taken together, the piperidol derivative B2 represents a promising lead compound for the combinational treatment of azole-resistant candidiasis.

Glass-cutting medical images via a mechanical image segmentation method based on crack propagation.

Medical image segmentation is crucial in diagnosing and treating diseases, but automatic segmentation of complex images is very challenging. Here we present a method, called the crack propagation method (CPM), based on the principles of fracture mechanics. This unique method converts the image segmentation problem into a mechanical one, extracting the boundary information of the target area by tracing the crack propagation on a thin plate with grooves corresponding to the area edge. The greatest advantage of CPM is in segmenting images involving blurred or even discontinuous boundaries, a task difficult to achieve by existing auto-segmentation methods. The segmentation results for synthesized images and real medical images show that CPM has high accuracy in segmenting complex boundaries. With increasing demand for medical imaging in clinical practice and research, this method will show its unique potential.

Drug Repurposing of Haloperidol: Discovery of New Benzocyclane Derivatives as Potent Antifungal Agents against Cryptococcosis and Candidiasis.

Despite the high morbidity and mortality of invasive fungal infections (IFIs), effective and safe antifungal agents are rather limited. Starting from antifungal lead compound haloperidol that was identified by drug repurposing, a series of novel benzocyclane derivatives were designed, synthesized, and assayed. Several compounds showed improved antifungal potency and broader antifungal spectra. Particularly, compound B10 showed good inhibitory activities against a variety of fungal pathogens and was proven to be an inhibitor of several virulence factors important for drug resistance. In the in vivo cryptococcosis and candidiasis models, compound B10 could effectively reduce the brain fungal burden of Cryptococcus neoformans and synergize with fluconazole to treat resistant Candida albicans infections. Preliminary antifungal mechanism studies revealed that compound B10 regained cell membrane damage and down-regulated the overexpression of ERG11 and MDR1 genes when used in combination with fluconazole. Taken together, haloperidol derivative B10 represents a promising lead compound for the development of a new generation of antifungal agents.

Discovery of Simplified Sampangine Derivatives with Potent Antifungal Activities against Cryptococcal Meningitis.

Cryptococcal meningitis (CM) is associated with high morbidity and mortality. Current antifungal drug therapy for CM has the following challenges: limited efficacy, significant side effects, emerging drug resistance, and unavailability in highly needed countries. There is an urgent need to develop novel CM therapeutic agents with a new mode of action. On the basis of the antifungal natural product sampangine, herein, novel simplified isoxazole derivatives were identified to possess excellent inhibitory activity against Cryptococcus neoformans (C. neoformans). Particularly, compound 9a was highly active (the minimum inhibitory concentration of 80% inhibition, MIC80 = 0.031 µg/mL) and significantly inhibited biofilm formation, melanin, and urease production of C. neoformans. 9a had good blood-brain barrier (BBB) permeability and effectively reduced the brain fungal burden in a murine model of cryptococcosis. The antifungal mechanism of compound 9a was preliminarily investigated by transmission electron microscopy and flow cytometry. It was able to cause necrocytosis of C. neoformans cells and cell cycle arrest in the G1/S phase. Isoxazole compound 9a represents a promising lead compound for the development of novel CM therapeutic agents.

Discovery of Carboline Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcal Meningitis.

Clinical treatment of cryptococcal meningitis (CM) remains a significant challenge because of the lack of effective and safe drug therapies. Developing novel CM therapeutic agents with novel chemical scaffolds and new modes of action is of great importance. Herein, new ß-hexahydrocarboline derivatives are shown to possess potent anticryptococcal activities. In particular, compound A4 showed potent in vitro and in vivo anticryptococcal activity with good metabolic stability and blood-brain barrier permeability. Compound A4 was orally active and could significantly reduce brain fungal burdens in a murine model of CM. Moreover, compound A4 could inhibit several virulence factors of Cryptococcus neoformans and might act by a new mode of action. Preliminary mechanistic studies revealed that compound A4 induced DNA double-stranded breaks and cell cycle arrest at the G2 phase by acting on the Cdc25c/CDK1/cyclin B pathway. Taken together, ß-hexahydrocarboline A4 represents a promising lead compound for the development of next-generation CM therapeutic agents.

In vivo measurements of human neck skin elasticity using MRI and finite element modeling.

PURPOSE: The assessment of mechanical properties of the human skin is very important in investigating the mechanism of obstructive sleep apnea, a common disorder characterized by repetitive collapse and obstruction of the upper airway during sleep. In this study, a unique method, combining magnetic resonance imaging (MRI) and finite element modeling (FEM), was developed to obtain the value of the in vivo elastic modulus of the neck skin. MEHTHOD: A total of 22 subjects, 16 males and six females, were recruited to participate in the MRI studies. The changes in the airway and the neck size resulting from fluid shift from the lower body to the neck were measured based on the MR images. A two-dimensional plane strain FE model was built to simulate such changes in the neck cross-section for each subject. RESULTS: Solving an inverse problem using FEM by matching the measured data, we obtained the in vivo elastic modulus of the neck skin to be 1.78 ± 1.73 MPa. Results showed that the elastic modulus tended to increase with age and body mass index for these subjects. A sensitivity analysis of the muscle and fat mechanical parameters was also performed to test their effects on the predicted skin elasticity. CONCLUSION: The unique method developed in this study for measuring the in vivo elastic modulus of the neck skin is quite effective, and the skin elasticity value obtained using this method is credible.